(a) Field of the invention
This invention relates to novel diazabicyclodecanones useful as antiarrhythmic agents. In particular, the invention relates to novel diazabicyclodecanones of the Formulas III and V which are useful in the treatment of arrhythmic disorders.
Arrhythmias are disorders relating to electrical impulse generation in the heart. The disorders include premature contractions (extrasystoles) originating in abnormal or ectopic foci in atria or ventricles, paroxysmal supraventricular tachycardia, atrial flutter, atrial fibrillation, and ventricular tachycardia and fibrillation. For a discussion on these disorders see for example the Pharmacological Basis of Therapeutics, Goodman and Gilman, the MacMillan Co., pgs. 709-711 (1970).
A number of compounds have been developed to alter cardiovascular function related to heart rate and rhythm. The cardiac glycosides, including digitalis, have as their main pharmacodynamic property the ability to increase the force of myocardial contraction. The salutary effects of these cardiac glycosides in congestive heart failure--increased cardiac output, decreased heart size, venous pressure and blood vlume; diuresis and relief of edema--are all explained on the basis of increased contractile force, a positive inotropic action. Quinidine is useful in the therapy of atrial fibrillation but exhibits several toxic reactions, such as cinchonism. The cardiac actions of procainamide are essentially identical to those for quinidine, and like quinidine, procainamide exhibits toxic side effects. Lidocaine, a widely used local anesthetic only administered intravenously may be used in the treatment of ectopic ventricular rhythms, but is not recommended for the treatment of supraventricular arrhythmias. Propranolol has found use in the treatment of supraventricular tachycardias and ventricular arrhythmias but because propranolol antagonizes adrenergic effects on contractility and because serious arrthymias are commonly encountered in the presence of overt or incipient heart failure, the use of the drug for its antiarrhythmic actions demands great care. Disopyramide is similar to procainamide and quinidine (referred to as a Type 1 antiarrhythmics). At therapeutic plasma levels disopyramide shortens the sinus node recovery time, lengthens the effective refractory period of the atrium and has a minimal effect on the effective refractory period of the AV mode. However, because of the anticholinergic effects of some of the Type 1 antiarrhythmics, they should not be used in patients with glaucoma, myasthenia gravis or problems of urinary retention.
(b) Prior Art
As previously described, a number of compounds are useful in the treatment of arrhythmias. The diazabicyclodecanones of the instant invention are novel and represent a new class of compounds useful to treat arrhythmias with reduced anticholinergic activity.